The racemic benzoquinoline compounds rel-(3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one (1), commonly known as Tetrabenazine, and a deuterated analogue thereof, rel-(3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d6) (2), commonly known as Deutetrabenazine, are vesicular monoamine transporter 2 (VMAT2) inhibitors. Tetrabenazine, which was first prepared in the 1950s, as described in, for example, U.S. Pat. No. 2,830,993 A, is marketed in the United States as XENAZINE®, and is indicated for the treatment of chorea associated with Huntington's disease. Deutetrabenazine, which is described in WO 2010/044981 A1, is marketed in the United States as AUSTEDO®, is also indicated for the treatment of chorea associated with Huntington's disease, as well for the treatment of tardive dyskinesia in adults.

Crystalline forms of Tetrabenazine are reported in WO 2012/081031 A1 and WO 2015/175505 A1, and those of Deutetrabenazine are reported in WO 2014/047167 A1. WO 2017/221169 A1 further reports crystalline pre-mixes of Deutetrabenazine with magnesium stearate and talc.
WO 2015/175505 A1 reports that XENAZINE® tablets are provided as an immediate release formulation. Tetrabenazine exhibits a pH-dependent solubility, having slight solubility at the low pH of the stomach, but being practically insoluble at pH values of greater than 4, which are present further down the gastrointestinal tract. As such, the immediate release formulation is intended to provide complete dissolution in the stomach. However, rapid dissolution from this formulation has been reported to lead to high peak plasma concentrations, which are believed to be associated with the occurrence side effects.
Modified/sustained release formulations of Tetrabenazine are disclosed in WO 2011/019956 A1 and WO 2015/175505 A1, which aim to alter the pharmacokinetic profile of Tetrabenazine, or metabolites thereof, and overcome problems associated with the immediate release formulation. However, owing to the low solubility of the Tetrabenazine in the higher pH regions of the gastrointestinal tract where the majority of the dissolution is expected to occur from a modified/sustained release formulation, there are concerns that complete dissolution of the administered dose may not occur for these types of formulations.
WO 2014/047167 A1 reports extended release formulations of Deutetrabenazine, which, together with the deuterium isotope effect, are expected to benefit patients by altering the pharmacokinetic profile of the drug substance. However, as for the modified release formulations of Tetrabenazine, problems could arise with extended release formulations as a result of the poor solubility of the active substance in the higher pH regions of the gastrointestinal tract.
Approaches to improving the solubility of a drug substance include, for example, particle size reduction techniques, dispersion of the drug substance onto an inert carrier, and formulation of the drug substance together with solubilizing excipients. A further approach, which is used in the modified release formulations described in WO 2015/175505 A1, comprises the use of an amorphous solid dispersion. However, amorphous forms tend to have lower stability compared to crystalline forms, and methods for their preparation can be complex on an industrial scale.
Different crystalline forms of the same compound may have different crystal packing, thermodynamic, spectroscopic, kinetic, surface and mechanical properties. For example, different crystalline forms may have different stability properties such that a particular crystalline form may be less sensitive to heat, relative humidity (RH) and/or light. Alternatively or additionally, a particular crystalline form may provide more favourable compressibility and/or density properties, thereby providing more desirable characteristics for formulation and/or product manufacturing. Differences in stability between solid forms of a drug may result from changes in chemical reactivity, such as differential oxidation. Particular crystalline forms may also have different solubilities, thereby providing different pharmacokinetic parameters, which allow for specific crystalline forms to be used in order to achieve specific pharmacokinetic targets. Differences in solubility between crystalline forms are particularly relevant for compounds exhibiting pH-dependent solubility, such as Tetrabenazine and Deutetrabenazine, wherein an enhancement in the solubility at higher pH values can provide an opportunity to prepare modified-release formulations where dissolution is possible further into the higher pH regions of the gastrointestinal tract, thereby delivering a greater percentage of drug per dose.
Although general approaches to the preparation of crystalline forms of active pharmaceutical ingredients are known, it is well established that the prediction of whether any given compound will exhibit polymorphism is not possible. Accordingly, it is not possible to extend generalities to the number and kinds of crystalline forms that can exist for Tetrabenazine and Deutetrabenazine, or to the methods that will be suitable for the preparation of any given crystalline form. Furthermore, prediction of the properties of any unknown crystalline forms, and how they will differ from other crystalline forms of the same compound, remains elusive (Joel Bernstein, Polymorphism in Molecular Crystals, Oxford University Press, New York, 2002, page 9).
In addition to the use of different crystalline forms to modify the physicochemical properties of a drug, it is also known that the physicochemical properties of a drug can be modified through the formation of co-crystals, wherein a drug molecule and a co-former co-crystallize within the same crystal lattice. However, methods are not available to predict the compounds that can successfully serve as co-formers with a particular drug or the conditions required to successfully co-crystallize two compounds within the same crystal lattice.
In view of the problems associated with the existing formulations of Tetrabenazine and Deutetrabenazine, there exists a need for novel crystalline forms of these compounds for use in the preparation of drug products providing improved properties, and methods for their manufacture.